Causal Inference of Metabolic Syndrome on Calcific Aortic Valve Stenosis: Linkage Disequilibrium Score Regression and Two-Sample, Two-Step Mendelian Randomization Analysis

1.1 Background This study aims to clarify the causal relationship between metabolic syndrome (MetS) and calcific aortic valve stenosis (CAVS) through Linkage Disequilibrium score regression (LDSC) and two-sample and two-step Mendelian randomization (MR). 1.2 Methods We conducted LDSC analysis and two-sample and two-step MR with Bayesian weighted MR validation using genome-wide association studies (GWAS) summary statistics. 1.3 Result LDSC analysis identified MetS and CAVS (rg = 0.264, p = 4.61×10 ^–26 ). In the two-sample MR study, Mets (P = 1.39×10 ^–20 , OR = 1.82), waist circumference (WC, p = 5.50×10 ^–10 , OR = 1.51), triglycerides (TG, p = 2.24×10 ^− 9 , OR = 1.42), and systolic blood pressure (SBP, p = 1.83×10 ^− 6 , OR = 1.04) were positively correlated with CAVS. In contrast, high-density lipoprotein (HDL-C, p = 0.002, OR = 0.9), and diastolic blood pressure (DBP, p = 0.002, OR = 0.78) were negatively correlated with CAVS. Two-step MR analysis indicated that among 233 circulating metabolites, 19 risk factors and 3 protective factors mediated the impacts of MetS, WC and TG on CAVS. 1.4 Conclusion MetS and CAVS share a common genetic architecture, with central adiposity, dyslipidemia, and blood pressure exhibiting distinct causal pathways. Small very-low-density lipoprotein particles, apolipoprotein B, and remnant cholesterol are key mediators linking MetS, WC, TG and CAVS.